The Opposing Roles of IVS2+691 CC Genotype and AC/AG Diplotype of 118A>G and IVS2+691G>C of OPRM1 Polymorphisms in Cold Pain Tolerance Among Opioid-Dependent Malay Males on Methadone Therapy
Pain Ther
The Opposing Roles of IVS2+691 CC Genotype and AC/ AG Diplotype of 118A>G and IVS2+691G>C of OPRM1 Polymorphisms in Cold Pain Tolerance Among Opioid- Dependent Malay Males on Methadone Therapy
Nasir Mohamad . Rusli Ismail 0 1 2 3 4 5 6 7
Malay 0 1 2 3 4 5 6 7
0 C. S. Lee Department of Emergency Medicine, School of Medical Sciences , USM, Kota Bharu, Kelantan , Malaysia
1 Z. Zahari C. S. Lee M. A. Ibrahim N. Musa M. A. M. Yasin S. C. Tan N. Mohamad R. Ismail Pharmacogenetics and Novel Therapeutics Cluster, Institute for Research in Molecular Medicine (INFORMM) , Universiti Sains Malaysia (USM), Kota Bharu, Kelantan , Malaysia
2 Z. Zahari (&) Department of Pharmacy, Hospital Universiti Sains Malaysia , Kota Bharu, Kelantan , Malaysia
3 R. Ismail Centre of Excellence for Research in AIDS (CERiA), University of Malaya , Kuala Lumpur , Malaysia
4 N. Mohamad Faculty of Medicine and Health Sciences, Universiti Sultan Zainal Abidin , Kuala Terengganu, Terengganu , Malaysia
5 Y. Y. Lee School of Medical Sciences, Universiti Sains Malaysia , Kota Bharu, Kelantan , Malaysia
6 M. A. M. Yasin Department of Psychiatry, School of Medical Sciences , USM, Kota Bharu, Kelantan , Malaysia
7 M. A. Ibrahim Department of Pharmacology and Toxicology, College of Pharmacy, Hawler Medical University , Erbil , Iraq
Introduction: We recently reported that a majority of opioid-dependent Malay males on methadone therapy are cold pain sensitive. It is postulated investigated the association between 118A[G rs2075572) variants on cold pain responses among were measured using the cold pressor test. DNA was extracted from the venous blood before
-
that
common
OPRM1
polymorphisms may be responsible. This study
Electronic supplementary material The online
version of this article (doi:10.1007/s40122-015-0041-y)
contains supplementary material, which is available to
authorized users.
chain
reaction
genotyping.
Repeated measures analysis of variance was used
to compare the cold pain responses and OPRM1
polymorphisms (118A[G and IVS2?691G[C)
using models including genotype dominant
and recessive models, allelic additive models,
and analysis of haplotypes and diplotypes.
Results: A total of 148 participants were
recruited. With the recessive model, those
with IVS2?691 homozygous CC genotype had
a shorter cold pain tolerance time than those
without CC genotype (i.e., GG/GC genotype;
29.81 vs. 43.08 s, respectively, P = 0.048). On
the other hand, with diplotype analysis,
participants with combined homozygous 118
AA genotype and heterozygous IVS2?691 GC
genotype (i.e., AC/AG diplotype) had a longer
cold pain tolerance time than those without
this diplotype (49.34 vs. 31.48 s, respectively,
P = 0.043). Cold pain threshold was not
associated with any of the 118A[G and
IVS2?691G[C variations despite being
analyzed using various models (all P[0.05).
Conclusion: The IVS2?691 CC genotype and
AC/AG diplotype of 118A[G and
IVS2?691G[C seem to have opposing roles in
pain tolerance among opioid-dependent Malay
males on methadone therapy. Haplotypes of
OPRM1 may be associated with altered binding
affinity.
INTRODUCTION
Malays; Methadone
dependence; Pain
The opioidergic neurotransmission system is an
important processor of painful stimuli [1–4].
The l-opioid receptor (OPRM1) is a primary
target for clinically important opioid analgesics,
including methadone. Studies among healthy
subjects showed a possible role of the opioid
receptor mu 1 gene (OPRM1) in altered pain
sensitivity [5, 6]. Genetic factors that affect the
density, function, and, consequently, the
signaling efficacy of l-opioid receptors may
contribute to inter-individual variations in the
pain response to opioids [7–9].
Southeast Asia is a highly populated and
cultural-diverse region with ethnic Malays
constituting the largest population group,
mainly populating countries including
Malaysia, Indonesia, and the southern part of
the Philippines. Males who are ethnic Malays
make up the majority of opioid-dependent
patients on methadone treatment in Malaysia
[
10
]. We have previously reported that a
majority of opioid-dependent Malay males on
methadone therapy are cold pain sensitive and
that the pain is frequently associated with poor
sleep quality [
11
]. One postulated mechanism
for altered pain sensitivity in this susceptible
population is polymorphisms in the OPRM1
gene.
Some of the most frequently studied
polymorphisms of OPRM1 include 118A[G
(dbSNP rs1799971), IVS2?691G[C (dbSNP
rs2075572), and IVS2?31G[A (dbSNP
rs9479757). The association between 118A[G
polymorphism and pressure pain was first
reported by Fillingim et al. [6] and Lotsch
et al. [5], but subsequent studies failed to
replicate these preliminary reports in different
experimental pain models and in different
populations [
12–14
]. Similarly, the roles of
other polymorphisms on pain sensitivity,
including IVS2?691G[C and IVS2?31G[A,
have been mixed. For example, the
IVS2?691G[C polymorphism did not increase
mo (...truncated)